Hepatocellular carcinoma (HCC) tumor microenvironment is more suppressive than colorectal cancer liver metastasis (CRLM) tumor microenvironment.
CXCR4
CXCR4 inhibitors
ENTPD1
Immune cells and the microenvironment
Inflammation-associated cancer
Liver cancer
Liver metastases
Liver microenvironment
Myeloid-derived suppressor cells
Regulatory T cells
Journal
Hepatology international
ISSN: 1936-0541
Titre abrégé: Hepatol Int
Pays: United States
ID NLM: 101304009
Informations de publication
Date de publication:
04 May 2023
04 May 2023
Historique:
received:
27
12
2022
accepted:
08
04
2023
medline:
5
5
2023
pubmed:
5
5
2023
entrez:
4
5
2023
Statut:
aheadofprint
Résumé
While HCC is an inflammation-associated cancer, CRLM develops on permissive healthy liver microenvironment. To evaluate the immune aspects of these two different environments, peripheral blood-(PB), peritumoral-(PT) and tumoral tissues-(TT) from HCC and CRLM patients were evaluated. 40 HCC and 34 CRLM were enrolled and freshly TT, PT and PB were collected at the surgery. PB-, PT- and TT-derived CD4 In HCC/CRLM-PB, higher number of functional Tregs, CD4 In HCC and CRLM, peripheral blood, peritumoral and tumoral tissues Tregs are highly represented and functional. Nevertheless, HCC displays a more immunosuppressive TME due to Tregs, MDSCs, intrinsic tumor features (CXCR4, CCL5, arginase) and the contest in which it develops. As CXCR4 is overexpressed in HCC/CRLM tumor/TME cells, CXCR4 inhibitors may be considered for double hit therapy in liver cancer patients.
Sections du résumé
BACKGROUND AND PURPOSE
OBJECTIVE
While HCC is an inflammation-associated cancer, CRLM develops on permissive healthy liver microenvironment. To evaluate the immune aspects of these two different environments, peripheral blood-(PB), peritumoral-(PT) and tumoral tissues-(TT) from HCC and CRLM patients were evaluated.
METHODS
METHODS
40 HCC and 34 CRLM were enrolled and freshly TT, PT and PB were collected at the surgery. PB-, PT- and TT-derived CD4
RESULTS
RESULTS
In HCC/CRLM-PB, higher number of functional Tregs, CD4
CONCLUSION
CONCLUSIONS
In HCC and CRLM, peripheral blood, peritumoral and tumoral tissues Tregs are highly represented and functional. Nevertheless, HCC displays a more immunosuppressive TME due to Tregs, MDSCs, intrinsic tumor features (CXCR4, CCL5, arginase) and the contest in which it develops. As CXCR4 is overexpressed in HCC/CRLM tumor/TME cells, CXCR4 inhibitors may be considered for double hit therapy in liver cancer patients.
Identifiants
pubmed: 37142825
doi: 10.1007/s12072-023-10537-6
pii: 10.1007/s12072-023-10537-6
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Associazione Italiana per la Ricerca sul Cancro
ID : IG-23218
Organisme : ERA-NET/TRANSCAN
ID : TRS-2016-00000341
Organisme : ERA-NET EURONANOMED
ID : EURONANOMED2019-044
Informations de copyright
© 2023. The Author(s).
Références
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–249
pubmed: 33538338
doi: 10.3322/caac.21660
Akinyemiju T, Abera S, Ahmed M, Alam N, Alemayohu MA, Global Burden of Disease Liver Cancer C, et al. The burden of primary liver cancer and underlying etiologies from 1990 to 2015 at the Global, Regional, and National Level: results from the Global Burden of Disease Study 2015. JAMA Oncol. 2017;3(12):1683–1691
pubmed: 28983565
pmcid: 5824275
doi: 10.1001/jamaoncol.2017.3055
Ringelhan M, Pfister D, O’Connor T, Pikarsky E, Heikenwalder M. The immunology of hepatocellular carcinoma. Nat Immunol. 2018;19(3):222–232
pubmed: 29379119
doi: 10.1038/s41590-018-0044-z
Yuan D, Huang S, Berger E, Liu L, Gross N, Heinzmann F, et al. Kupffer cell-derived tnf triggers cholangiocellular tumorigenesis through JNK due to chronic mitochondrial dysfunction and ROS. Cancer Cell. 2017;31(6):771-789 e776
pubmed: 28609656
pmcid: 7909318
doi: 10.1016/j.ccell.2017.05.006
Volponi C, Gazzillo A, Bonavita E. The tumor microenvironment of hepatocellular carcinoma: untying an intricate immunological network. Cancers. 2022;14(24):6151
pubmed: 36551635
pmcid: 9776867
doi: 10.3390/cancers14246151
Zhang Q, Lou Y, Yang J, Wang J, Feng J, Zhao Y, et al. Integrated multiomic analysis reveals comprehensive tumour heterogeneity and novel immunophenotypic classification in hepatocellular carcinomas. Gut. 2019;68(11):2019–2031
pubmed: 31227589
doi: 10.1136/gutjnl-2019-318912
Correia AL, Guimaraes JC, der Auf Maur P, De Silva D, Trefny MP, Okamoto R, et al. Hepatic stellate cells suppress NK cell-sustained breast cancer dormancy. Nature. 2021;594(7864):566–571
pubmed: 34079127
doi: 10.1038/s41586-021-03614-z
Jenne CN, Kubes P. Immune surveillance by the liver. Nat Immunol. 2013;14(10):996–1006
pubmed: 24048121
doi: 10.1038/ni.2691
Yu X, Zhu L, Liu J, Xie M, Chen J, Li J. Emerging role of immunotherapy for colorectal cancer with liver metastasis. Onco Targets Ther. 2020;13:11645–11658
pubmed: 33223838
pmcid: 7671511
doi: 10.2147/OTT.S271955
Hou J, Zhang H, Sun B, Karin M. The immunobiology of hepatocellular carcinoma in humans and mice: basic concepts and therapeutic implications. J Hepatol. 2020;72(1):167–182
pubmed: 31449859
doi: 10.1016/j.jhep.2019.08.014
Garnelo M, Tan A, Her Z, Yeong J, Lim CJ, Chen J, et al. Interaction between tumour-infiltrating B cells and T cells controls the progression of hepatocellular carcinoma. Gut. 2017;66(2):342–351
pubmed: 26669617
doi: 10.1136/gutjnl-2015-310814
Langhans B, Nischalke HD, Kramer B, Dold L, Lutz P, Mohr R, et al. Role of regulatory T cells and checkpoint inhibition in hepatocellular carcinoma. Cancer Immunol Immunother. 2019;68(12):2055–2066
pubmed: 31724091
doi: 10.1007/s00262-019-02427-4
Heymann F, Peusquens J, Ludwig-Portugall I, Kohlhepp M, Ergen C, Niemietz P, et al. Liver inflammation abrogates immunological tolerance induced by Kupffer cells. Hepatology. 2015;62(1):279–291
pubmed: 25810240
doi: 10.1002/hep.27793
Zhou SL, Dai Z, Zhou ZJ, Wang XY, Yang GH, Wang Z, et al. Overexpression of CXCL5 mediates neutrophil infiltration and indicates poor prognosis for hepatocellular carcinoma. Hepatology. 2012;56(6):2242–2254
pubmed: 22711685
doi: 10.1002/hep.25907
Liu LZ, Zhang Z, Zheng BH, Shi Y, Duan M, Ma LJ, et al. CCL15 Recruits suppressive monocytes to facilitate immune escape and disease progression in hepatocellular carcinoma. Hepatology. 2019;69(1):143–159
pubmed: 30070719
doi: 10.1002/hep.30134
Sun L, Xu G, Liao W, Yang H, Xu H, Du S, et al. Clinicopathologic and prognostic significance of regulatory T cells in patients with hepatocellular carcinoma: a meta-analysis. Oncotarget. 2017;8(24):39658–39672
pubmed: 28487498
pmcid: 5503641
doi: 10.18632/oncotarget.17340
Eggert T, Greten TF. Tumor regulation of the tissue environment in the liver. Pharmacol Ther. 2017;173:47–57
pubmed: 28167218
pmcid: 5408316
doi: 10.1016/j.pharmthera.2017.02.005
Brudvik KW, Henjum K, Aandahl EM, Bjornbeth BA, Tasken K. Regulatory T-cell-mediated inhibition of antitumor immune responses is associated with clinical outcome in patients with liver metastasis from colorectal cancer. Cancer Immunol Immunother. 2012;61(7):1045–1053
pubmed: 22159472
doi: 10.1007/s00262-011-1174-4
Dagenborg VJ, Marshall SE, Yaqub S, Grzyb K, Boye K, Lund-Iversen M, et al. Neoadjuvant chemotherapy is associated with a transient increase of intratumoral T-cell density in microsatellite stable colorectal liver metastases. Cancer Biol Ther. 2020;21(5):432–440
pubmed: 32098573
pmcid: 7515522
doi: 10.1080/15384047.2020.1721252
Mantovani A, Marchesi F, Malesci A, Laghi L, Allavena P. Tumour-associated macrophages as treatment targets in oncology. Nat Rev Clin Oncol. 2017;14(7):399–416
pubmed: 28117416
pmcid: 5480600
doi: 10.1038/nrclinonc.2016.217
Zhou H, Liu Z, Wang Y, Wen X, Amador EH, Yuan L, et al. Colorectal liver metastasis: molecular mechanism and interventional therapy. Signal Transduct Target Ther. 2022;7(1):70
pubmed: 35246503
pmcid: 8897452
doi: 10.1038/s41392-022-00922-2
Wang Q, Feng M, Yu T, Liu X, Zhang P. Intratumoral regulatory T cells are associated with suppression of colorectal carcinoma metastasis after resection through overcoming IL-17 producing T cells. Cell Immunol. 2014;287(2):100–105
pubmed: 24487033
doi: 10.1016/j.cellimm.2014.01.002
Polimeno NM, Ierano C, D’Alterio C, Losito NS, Napolitano M, Portella L, et al. CXCR4 expression affects overall survival of HCC patients whereas CXCR7 expression does not. Cell Mol Immunol. 2015;12(4):474–482
doi: 10.1038/cmi.2014.102
Ottaiano A, Santorsola M, Del Prete P, Perri F, Scala S, Caraglia M, et al. Prognostic significance of CXCR4 in colorectal cancer: an updated meta-analysis and critical appraisal. Cancers. 2021;13(13):3284
pubmed: 34209026
pmcid: 8269109
doi: 10.3390/cancers13133284
Urosevic J, Blasco MT, Llorente A, Bellmunt A, Berenguer-Llergo A, Guiu M, et al. ERK1/2 signaling induces upregulation of ANGPT2 and CXCR4 to mediate liver metastasis in colon cancer. Cancer Res. 2020;80(21):4668–4680
pubmed: 32816905
doi: 10.1158/0008-5472.CAN-19-4028
Tan HX, Gong WZ, Zhou K, Xiao ZG, Hou FT, Huang T, et al. CXCR4/TGF-beta1 mediated hepatic stellate cells differentiation into carcinoma-associated fibroblasts and promoted liver metastasis of colon cancer. Cancer Biol Ther. 2020;21(3):258–268
pubmed: 31825725
doi: 10.1080/15384047.2019.1685157
D’Alterio C, Nasti G, Polimeno M, Ottaiano A, Conson M, Circelli L, et al. CXCR4-CXCL12-CXCR7, TLR2-TLR4, and PD-1/PD-L1 in colorectal cancer liver metastases from neoadjuvant-treated patients. Oncoimmunology. 2016;5(12): e1254313
pubmed: 28123896
pmcid: 5214751
doi: 10.1080/2162402X.2016.1254313
Song JS, Chang CC, Wu CH, Dinh TK, Jan JJ, Huang KW, et al. A highly selective and potent CXCR4 antagonist for hepatocellular carcinoma treatment. Proc Natl Acad Sci U S A. 2021. https://doi.org/10.1073/pnas.2015433118
doi: 10.1073/pnas.2015433118
pubmed: 34921118
pmcid: 8740576
Chen Y, Ramjiawan RR, Reiberger T, Ng MR, Hato T, Huang Y, et al. CXCR4 inhibition in tumor microenvironment facilitates anti-programmed death receptor-1 immunotherapy in sorafenib-treated hepatocellular carcinoma in mice. Hepatology. 2015;61(5):1591–1602
pubmed: 25529917
doi: 10.1002/hep.27665
Righi E, Kashiwagi S, Yuan J, Santosuosso M, Leblanc P, Ingraham R, et al. CXCL12/CXCR4 blockade induces multimodal antitumor effects that prolong survival in an immunocompetent mouse model of ovarian cancer. Cancer Res. 2011;71(16):5522–5534
pubmed: 21742774
pmcid: 3959864
doi: 10.1158/0008-5472.CAN-10-3143
Santagata S, Napolitano M, D’Alterio C, Desicato S, Maro SD, Marinelli L, et al. Targeting CXCR4 reverts the suppressive activity of T-regulatory cells in renal cancer. Oncotarget. 2017;8(44):77110–77120
pubmed: 29100374
pmcid: 5652768
doi: 10.18632/oncotarget.20363
Nakabayashi H, Taketa K, Miyano K, Yamane T, Sato J. Growth of human hepatoma cells lines with differentiated functions in chemically defined medium. Cancer Res. 1982;42(9):3858–3863
pubmed: 6286115
Kasai F, Hirayama N, Ozawa M, Satoh M, Kohara A. HuH-7 reference genome profile: complex karyotype composed of massive loss of heterozygosity. Hum Cell. 2018;31(3):261–267
pubmed: 29774518
pmcid: 6002425
doi: 10.1007/s13577-018-0212-3
Kawamoto M, Yamaji T, Saito K, Shirasago Y, Satomura K, Endo T, et al. Identification of characteristic genomic markers in human hepatoma HuH-7 and Huh7.5.1-8 cell lines. Front Genet. 2020;11:546106
pubmed: 33193621
pmcid: 7581915
doi: 10.3389/fgene.2020.546106
Oz O, Iscan E, Batur T, Ozturk M. 3D Organoid modelling of hepatoblast-like and mesenchymal-like hepatocellular carcinoma cell lines. Hepatoma Research. 2021;7:60
Di Maro S, Trotta AM, Brancaccio D, Di Leva FS, La Pietra V, Ieranò C, et al. Exploring the N-terminal region of C-X-C motif chemokine 12 (CXCL12): identification of plasma-stable cyclic peptides as novel, potent C-X-C chemokine receptor type 4 (CXCR4) antagonists. J Med Chem. 2016;59(18):8369–8380
pubmed: 27571038
doi: 10.1021/acs.jmedchem.6b00695
Miyara M, Yoshioka Y, Kitoh A, Shima T, Wing K, Niwa A, et al. Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity. 2009;30(6):899–911
pubmed: 19464196
doi: 10.1016/j.immuni.2009.03.019
Krijgsman D, de Vries NL, Skovbo A, Andersen MN, Swets M, Bastiaannet E, et al. Characterization of circulating T-, NK-, and NKT cell subsets in patients with colorectal cancer: the peripheral blood immune cell profile. Cancer Immunol Immunother. 2019;68(6):1011–1024
pubmed: 31053876
pmcid: 6529387
doi: 10.1007/s00262-019-02343-7
Schoenberg MB, Zhu T, Hao J, Bucher JN, Li X, Li X, et al. Highly differential count of circulating and tumor infiltrating immune cells in patients with non-HCV/non-HBV hepatocellular carcinoma. Cancer Immunol Immunother. 2022;71(5):1103–1113
pubmed: 34585256
doi: 10.1007/s00262-021-03061-9
Ohue Y, Nishikawa H. Regulatory T (Treg) cells in cancer: can Treg cells be a new therapeutic target? Cancer Sci. 2019;110(7):2080–2089
pubmed: 31102428
pmcid: 6609813
doi: 10.1111/cas.14069
Li DY, Xiong XZ. ICOS(+) Tregs: a functional subset of Tregs in immune diseases. Front Immunol. 2020;11:2104
pubmed: 32983168
pmcid: 7485335
doi: 10.3389/fimmu.2020.02104
Pedroza-Gonzalez A, Verhoef C, Ijzermans JN, Peppelenbosch MP, Kwekkeboom J, Verheij J, et al. Activated tumor-infiltrating CD4+ regulatory T cells restrain antitumor immunity in patients with primary or metastatic liver cancer. Hepatology. 2013;57(1):183–194
pubmed: 22911397
doi: 10.1002/hep.26013
Timperi E, Barnaba V. CD39 regulation and functions in T Cells. Int J Mol Sci. 2021;22(15):8068
pubmed: 34360833
pmcid: 8348030
doi: 10.3390/ijms22158068
Wegrzyn AS, Kedzierska AE, Obojski A. Identification and classification of distinct surface markers of T regulatory cells. Front Immunol. 2022;13:1055805
pubmed: 36741366
doi: 10.3389/fimmu.2022.1055805
Künzli BM, Bernlochner MI, Rath S, Käser S, Csizmadia E, Enjyoji K, et al. Impact of CD39 and purinergic signalling on the growth and metastasis of colorectal cancer. Purinergic Signal. 2011;7(2):231–241
pubmed: 21484085
pmcid: 3146639
doi: 10.1007/s11302-011-9228-9
Cai XY, Ni XC, Yi Y, He HW, Wang JX, Fu YP, et al. Overexpression of CD39 in hepatocellular carcinoma is an independent indicator of poor outcome after radical resection. Medicine. 2016;95(40): e4989
pubmed: 27749555
pmcid: 5059057
doi: 10.1097/MD.0000000000004989
Szeponik L, Ahlmanner F, Sundström P, Rodin W, Gustavsson B, Bexe Lindskog E, et al. Intratumoral regulatory T cells from colon cancer patients comprise several activated effector populations. BMC Immunol. 2021;22(1):58
pubmed: 34407765
pmcid: 8375143
doi: 10.1186/s12865-021-00449-1
Moesta AK, Li XY, Smyth MJ. Targeting CD39 in cancer. Nat Rev Immunol. 2020;20(12):739–755
pubmed: 32728220
doi: 10.1038/s41577-020-0376-4
Chen H, Zhou XH, Li JR, Zheng TH, Yao FB, Gao B, et al. Neutrophils: driving inflammation during the development of hepatocellular carcinoma. Cancer Lett. 2021;522:22–31
pubmed: 34517084
doi: 10.1016/j.canlet.2021.09.011
Hu F, Miao L, Zhao Y, Xiao YY, Xu Q. A meta-analysis for C-X-C chemokine receptor type 4 as a prognostic marker and potential drug target in hepatocellular carcinoma. Drug Des Devel Ther. 2015;9:3625–3633
pubmed: 26203228
pmcid: 4507792
doi: 10.2147/DDDT.S86032
Li B, Zeng Y, Reeves PM, Ran C, Liu Q, Qu X, et al. AMD3100 augments the efficacy of mesothelin-targeted, immune-activating VIC-008 in mesothelioma by modulating intratumoral immunosuppression. Cancer Immunol Res. 2018;6(5):539–551
pubmed: 29511032
doi: 10.1158/2326-6066.CIR-17-0530
Xu Y, Fang F, Jiao H, Zheng X, Huang L, Yi X, et al. Activated hepatic stellate cells regulate MDSC migration through the SDF-1/CXCR4 axis in an orthotopic mouse model of hepatocellular carcinoma. Cancer Immunol Immunother. 2019;68(12):1959–1969
pubmed: 31641797
doi: 10.1007/s00262-019-02414-9
Wang S, Gao S, Li Y, Qian X, Luan J, Lv X. Emerging importance of chemokine receptor CXCR4 and its ligand in liver disease. Front Cell Dev Biol. 2021;9: 716842
pubmed: 34386499
pmcid: 8353181
doi: 10.3389/fcell.2021.716842
Strouhalova K, Prechova M, Gandalovicova A, Brabek J, Gregor M, Rosel D. Vimentin intermediate filaments as potential target for cancer treatment. Cancers. 2020;12(1):184
pubmed: 31940801
pmcid: 7017239
doi: 10.3390/cancers12010184
Chang L, Li C, Lan T, Wu L, Yuan Y, Liu Q, et al. Decreased expression of long non-coding RNA GAS5 indicates a poor prognosis and promotes cell proliferation and invasion in hepatocellular carcinoma by regulating vimentin. Mol Med Rep. 2016;13(2):1541–1550
pubmed: 26707238
doi: 10.3892/mmr.2015.4716
Deng J, Jiang R, Meng E, Wu H. CXCL5: A coachman to drive cancer progression. Front Oncol. 2022;12: 944494
pubmed: 35978824
pmcid: 9376318
doi: 10.3389/fonc.2022.944494
Grzywa TM, Sosnowska A, Matryba P, Rydzynska Z, Jasinski M, Nowis D, et al. Myeloid cell-derived arginase in cancer immune response. Front Immunol. 2020;11:938
pubmed: 32499785
pmcid: 7242730
doi: 10.3389/fimmu.2020.00938
Singh SK, Mishra MK, Rivers BM, Gordetsky JB, Bae S, Singh R. Biological and clinical significance of the CCR5/CCL5 axis in hepatocellular carcinoma. Cancers. 2020;12(4):883
pubmed: 32260550
pmcid: 7226629
doi: 10.3390/cancers12040883
Haist M, Stege H, Grabbe S, Bros M. The functional crosstalk between myeloid-derived suppressor cells and regulatory T cells within the immunosuppressive tumor microenvironment. Cancers. 2021;13(2):210
pubmed: 33430105
pmcid: 7827203
doi: 10.3390/cancers13020210
You J, Chen W, Chen J, Zheng Q, Dong J, Zhu Y. The oncogenic role of ARG1 in progression and metastasis of hepatocellular carcinoma. Biomed Res Int. 2018;2018:2109865
pubmed: 30320132
pmcid: 6167590
doi: 10.1155/2018/2109865
Halama N, Zoernig I, Berthel A, Kahlert C, Klupp F, Suarez-Carmona M, et al. Tumoral immune cell exploitation in colorectal cancer metastases can be targeted effectively by anti-CCR5 therapy in cancer patients. Cancer Cell. 2016;29(4):587–601
pubmed: 27070705
doi: 10.1016/j.ccell.2016.03.005